As published in JACS, researchers in the Johnson Group have developed a highly diastereoselective synthesis of 2,6-cis-disubstituted tetrahydropyrans (THPs) via Lewis acid-catalyzed formal [4 + 2] cycloaddition of donor−acceptor cyclobutanes and aldehydes. THP products are formed in up to 96% yield and 99:1 diastereoselectivity.
Aromatic, cinnamyl, and aliphatic aldehydes are competent dipolarophiles in this system. This methodology was extended to a [[2 + 2] + 2] cycloaddition of 4-methoxystyrene, dimethyl methylidene malonate, and an aldehyde to furnish THPs directly without prior isolation of the cyclobutane.
As published in JACS, researchers in the Murray Group show how oxidation of dissolved 1.6 ± 0.6 nm (dia.) IrIVOx nanoparticles in pH 13 solutions leads to a 100% current efficient oxidation of water to O2, at a modest overpotential η of only 0.29 V, relative to thermodynamic expectations for the four electron H2O→O2 reaction.
Each nanoparticle contains an average of 66 Ir sites; all are electroactive, so that the nanoparticles act, effectively, as 66 electron transfer mediators in the water oxidation. Each Ir site has a turnover frequency (TO, mol O2/Ir sites/s) of 8−11 s−1, which is nearly the same as observed for films of IrIVOx nanoparticle composed of similar nanoparticles, and providing the first comparison of electrocatalysis by nanoparticle films with redox catalysis by dissolved, diffusing nanoparticles.
As published in Organic Letters, the Gagné Group has shown that the resting state of a gold(I)-catalyzed hydroarylation reaction changes in the presence of Ag+, with silver free catalysts resting at a dinuclear gold and Ag+ containing solutions resting at a heteronuclear gold-silver species with an asymmetric 3-center-2-electron Au-C-Ag bond stablizied by an auro-argentophilic interaction.
Adventitious Ag+, typically from LAuCl activation, can therefore intercept key organogold intermediates and effect the catalysis even when it does not effect the reaction in Au free control experiments. Key observations point to Ag+ ions intercepting Au(I) catalytic intermediates and subsequently effecting catalyst speciation and reaction kinetics; a structural model is also suggested. The discovery of dinuclear gold-silver intermediates may rationalize known Ag+ effects in gold(I) catalysis.
The Baer Group has published a threshold photoelectron photoion coincidence study in which the energy required to dissociatively ionize propene (C3H6 + hv → C3H5+ + H + e-) was measured to be 11.898 ± 0.024 eV. When this is combined with a recently reported ionization energy of the allyl radical, see Figure below, a high precision propene C-H bond energy (BE) as well as the proton affinity (PA) of allene could be established.
This study was complicated by the slow dissociation of the propene ion, which caused previous investigations to be too high, thereby underestimating the PA and overestimating the BE. The Baer group established the correct dissociation onset by measuring the dissociation rate constants as a function of the ion energy by time of flight mass spectrometry, and extrapolating the rate to the dissociation onset.
The chromatin folding problem is an exciting and rich field for modern research. On the most basic level, chromatin fiber consists of a collection of protein-nucleic acid complexes, known as nucleosomes, joined together by segments of linker DNA. Understanding how the cell successfully compacts meters of highly charged DNA into a micrometer size nucleus while still enabling rapid access to the genetic code for transcriptional processes is a challenging goal.
In an article published in JACS, the Papoian Group, discusses the way mobile ions condense around the nucleosome core particle, as revealed by an extensive all-atom molecular dynamics simulation. Overall, this research facilitates a better understanding of the way ionic and hydration interactions within a nucleosome may affect internucleosomal interactions in higher order chromatin fibers.
Researchers in the Waters Group, as published in JACS, demonstrate how phosphorylated amino acids were incorporated into a designed β-hairpin peptide to study the effect on β-hairpin structure when the phosphate group is positioned to interact with a tryptophan residue on the neighboring strand. The three commonly phosphorylated residues in biological systems, serine, threonine, and tyrosine, were studied in the same β-hairpin system.
It was found that phosporylation destabilizes the hairpin structure by approximately 1.0 kcal/mol, regardless of the type of phosphorylated residue. In contrast, destabilization due to glutamic acid was about 0.3 kcal/mol. Double mutant cycles and pH studies are consistent with a repulsive interaction as the source of destabilization. These findings demonstrate a novel mechanism by which phosphorylation may influence protein structure and function.
As published in the Journal of Molecular Biology, in collaboration with researchers from UNC's Department of Biology, investigators in the Redinbo Group show how the majority of eukaryotic pre-mRNAs are processed by 3'-end cleavage and polyadenylation. The complex responsible contains the ~1160-residue protein Symplekin. The structure and dynamics of the Symplekin N-terminal HEAT domain were investigated to begin elucidating the role Symplekin plays in mRNA maturation. The crystal structure of the Drosophila melanogaster Symplekin HEAT domain was determined to 2.4 Å resolution with single-wavelength anomalous dispersion phasing methods.
Molecular dynamics simulations of this domain show that the presence of a unique loop dampens correlated and anticorrelated motion in the HEAT domain, therefore providing a neutral surface for potential protein–protein interactions. HEAT domains are often employed for such macromolecular contacts. Together, these data support the conclusion that the Symplekin HEAT domain serves as a scaffold for protein–protein interactions essential to the mRNA maturation process.
Protein tyrosine phosphatases (PTPs) regulate a broad range of cellular processes including proliferation, differentiation, migration, apoptosis, and immune responses. Dysfunction of PTP activity is associated with cancers, metabolic syndromes, and autoimmune disorders. Consequently, small molecule PTP inhibitors should serve not only as powerful tools to delineate the physiological roles of these enzymes in vivo but also as lead compounds for therapeutic development.
In a collaborative work published in JACS, the Lawrence Group describes a novel stepwise fluorophore-tagged combinatorial library synthesis and competitive fluorescence polarization screening approach that transforms a weak and general PTP inhibitor into an extremely potent and selective TC-PTP inhibitor with highly efficacious cellular activity. The result serves as a proof-of-concept in PTP inhibitor development, as it demonstrates the feasibility of acquiring potent, yet highly selective, cell permeable PTP inhibitory agents. Given the general nature of the approach, this strategy should be applicable to other PTP targets.
The platinum-containing chemotherapeutic cisplatin is the first-line treatment for many types of cancer, but results in a myriad of disparaging dose-limiting side effects, such as nephrotoxicity and neurotoxicity. Nanomaterials have shown great promise in selectively delivering chemotherapeutics to tumors to reduce these side effects and to increase therapeutic indices. As reported in JACS, the Lin Group has developed a novel nanovector platform based on nanoscale metal-organic frameworks, NMOFs, for delivering chemotherapeutics and imaging contrast agents.
NMOFs are materials crafted from metals and organic bridging ligands, and can be engineered to contain reactive functional groups. In this study, the amino groups incorporated into the NMOFs were used to graft optical imaging contrast agents or platinum-containing chemotherapeutics. These modified NMOFs were coated in silica to reduce premature release of imaging contrast agents or chemotherapeutics before arriving at the tumor sites. Preliminary in vitro tests showed that these NMOFs could effectively cause cell death in human colon cancer cell cultures with an efficacy similar to cisplatin. The Lin Group hopes to further modify this strategy to deliver other cancer drugs and imaging contrast agents.
Published in JACS, the Murray Group reports how electrospray ionization triple-quadrupole mass spectrometry of ca. 1.6 nm diameter thiolate-protected gold nanoparticles has been achieved at higher resolution than in previous reports. The results reveal the presence of nanoparticles with formulas Au144L60 and Au146L59, present in the sample as a mixture.
The improved resolution is based on lowering m/z by exchanging multiple [−SC11H22N(CH2CH3)3+] ligands into the original [−S(CH2)5CH3] ligand shell. The nanoparticles are thus intrinsically cationized and appear as a series of 10+ to 15+ mass spectral peaks. The assigned state of charge was confirmed by a collision-induced dissociation measurement.
To generate model substrates for cell adhesion, the Yousaf Group has developed two different biocompatible strategies based on self-assembled monolayers (SAMs) of alkanethiolates on gold terminated with latent ketones and aldehydes. Under spatial control, the hydroquinone and alcohol terminated SAMs can be oxidized to allow for oxyamine ligand patterning on the surface with microfluidic cassettes. These immobilization strategies were characterized by electrochemistry and fluorescence microscopy. By utilizing a cell adhesive peptide, cell patterns were also generated.
These methods are of broad utility to the research community as an easily accessible chemoselective strategy to immobilize ligands to surfaces. Previous immobilization strategies require multistep synthesis to generate the reactive head group on the surface. The Yousaf method requires either a simple synthesis or commercially available materials. The many different functional groups compatible with carbonyl chemistry allow for a range of ligands to be immobilized. In the future, the ability to oxidize hydroxy terminated SAMs may be extended to tailor a broad range of materials for molecular electronic and biological sensing applications.
Under experimental conditions chosen to establish constitutional equilibration, it is possible to amplify unusual structures that maximally lower the system free energy. In cases where a template is added to the system, new host-guest pairs can be identified from complex mixtures. The Gagné Group has discovered a situation where one of the components recognizes itself and interlocks two 56-membered rings, each of which is composed of 1 A unit and 3 B units.
The X-ray structure shows two rings mutually grabbing each other. The self-recognition occurs via the usual suspects of protein recognition; π-stacking, H-bonding, and C-H–π interactions. NMR analysis shows that the solid state structure is maintained in solution, and thus serves as an excellent structural model for cases where these subunits assemble into tight-binding hosts for various guests.
As reported in the October 23, 2009, issue of the journal Science, Carolina chemists in collaboration with colleagues at the University of Washington have taken an important step in converting methane gas to a liquid, potentially making it more useful as a fuel and as a source for making other chemicals.
The carbon-hydrogen bonds of alkanes are weak ligands and thus reports of isolation or spectroscopic observation of alkane complexes in solution are extremely rare. Nevertheless, such complexes are postulated as intermediates that form prior to C-H bond scission in most oxidative addition reactions of alkanes. The Shilov system for catalytic conversion of methane to methanol is thought to involve a Pt(II) methane complex as a key intermediate. While a postdoctoral fellow in the Brookhart Group, Wes Bernskoetter, now on the faculty at Brown, succeeded in preparing the first solution-stable, NMR-observable transition metal complex of the simplest alkane, methane (CH4).
The methane complex was obtained by low temperature protonation of a pincer rhodium methyl complex and fully characterized by 1H, 13C and 31P NMR spectroscopy. Cindy Schauer, co-author of the study, carried out DFT calculations that suggest one C-H bond interacts preferentially with the Rh center to form a three-center, two-electron bond, as per the above figure. The Brookhart Group hopes that investigation of the properties of this and other methane complexes may lead to more efficient catalysts for functionalization of alkanes.
Researchers in the Berkowitz Group performed molecular dynamics simulations on systems containing phosphatidycholine headgroups attached to graphene plates (PC−headgroup plates) immersed in water to study the interaction between phosphatidylcholine bilayers in water. The potential of mean force (PMF) between PC−headgroup plates shows that the interaction is repulsive.
As described in The Journal of Physical Chemistry B, the investigators observed three distinct regimes in the PMF depending on the interplate distances: the small distance regime, intermediate distance regime, and large distance regime. The researchers believe that the repulsive interaction in the intermediate interplate distance regime is associated with the hydration force due to the removal of water molecules adjacent to the headgroups.
Protein−protein interaction is the fundamental step of biological signal transduction. Interacting proteins find each other by diffusion. To gain insight into diffusion under the crowded conditions found in cells, researchers in the Pielak Group used nuclear magnetic resonance spectroscopy (NMR) to measure the effects of solvent additives on the translational and rotational diffusion of the 7.4 kDa globular protein, chymotrypsin inhibitor 2.
The additives were glycerol and the macromolecular crowding agent, polyvinyl pyrrolidone (PVP). As published in the Journal of Physical Chemistry B, both translational diffusion and rotational diffusion decrease with increasing solution viscosity. For glycerol, the decrease obeys the Stokes−Einstein and Stokes−Einstein Debye laws. Three types of deviation are observed for PVP: the decrease in diffusion with increased viscosity is less than predicted, this negative deviation is greater for rotational diffusion, and the negative deviation increases with increasing PVP molecular weight.
Cellular RNA molecules undergo complex folding transitions to form specific, biologically active, three-dimensional structures. A persistent and poorly explained observation is that many RNAs fold very slowly, on timescales requiring minutes or longer. Slow folding ultimately governs the rate at which an RNA can perform its biological function.
In work reported in PNAS, Stefanie Mortimer in the Weeks Lab used time-resolved SHAPE chemistry to show that slow folding at a single nucleotide in the unusual C2'-endo conformation constitutes the rate-determining step for folding a large 50 kDa RNA. Nucleotides in the C2'-endo conformation are relatively rare but are highly overrepresented in functionally critical RNA motifs. This work thus identifies a surprisingly simple, but likely ubiquitous, mechanism for controlling biological processes involving RNA.
Serotonin, also known as 5-HT is an important molecule in the brain that is implicated in mood and emotional processes. Although there is a heavy pharmaceutical emphasis on serotonin's involvement in many neurological disorders, in vivo, its dynamic release and uptake kinetics are poorly understood. This is due to a lack of analytical techniques for its rapid measurement. Whereas fast-scan cyclic voltammetry with carbon fiber microelectrodes is used frequently to monitor subsecond dopamine release in freely moving and anesthetized rats, the electrooxidation of serotonin forms products that quickly polymerize and irreversibly coat the carbon electrode surface.
In a paper published in Analytical Chemistry, the Wightman Group identifies the root of this fouling to not only be due to serotonin, but also to the negatively charged extracellular metabolites of serotonin, present in 200−1000 times the concentration of serotonin in vivo. To impede access of these negatively charged species, a thin layer of Nafion, a cation exchange polymer, was electrodeposited onto cylindrical carbon-fiber microelectrodes. The team visually confirmed the presence of the Nafion film using scanning electron microscopy and showed that the signals for negatively charged species were diminished. Interestingly, the properties of the Nafion also increased sensitivity to serotonin, providing an electrochemical signature of serotonin that could be verified in vitro. In vivo, the team used physiological, anatomical, and pharmacological evidence to validate the signal as serotonin. Using Nafion-modified microelectrodes, the Wightman Group presents the first endogenous recording of serotonin in the mammalian brain.